L-3-phosphoserine phosphatase (L3PSP) is a widely expressed member of the haloacid dehalogenase (HAD) superfamily and its enzyme activity is the irreversible and rate limiting step in L-serine biosynthesis. Dysregulation of L-serine biosynthesis is featured in neurological disorders, Williams-Beuren syndrome, skin ichthyosis and a variety of epithelial neoplasms. However, the significance of altered L3PSP activity on the initiation and course of these diseases is still not clear. We recently identified L3PSP by microarray analysis to be altered in an integrin transgenic mouse model that is predisposed to epidermal hyperplasia and skin inflammation indicating that L3PSP may be a critical regulator of epidermal homeostasis. The goal of this proposal is to define the role for L3PSP in skin development and epidermal disease. Our preliminary results show that ectopic expression of L3PSP in the proliferative layer of the epidermis leads to defects in hair follicle morphogenesis, decreased hair follicle number and dysregulated hair follicle cycling. We have also uncovered novel L3PSP interaction candidate proteins that function in sumoylation pathways and proteins that mediate Fas ligand apoptosis. We will determine if the effects of L3PSP expression in disrupted hair follicle growth and cycling are dependent on its phosphatase activity and if L3PSP expression stimulates epidermal keratinocytes to undergo apoptosis. To demonstrate a new role(s) for L3PSP outside of L-serine biosynthesis we will conduct biochemical studies to validate putative interactions between L3PSP and candidate proteins identified by yeast two-hybrid analysis. Finally, to determine the requirement for L3PSP in epidermal homeostasis we will generate murine and human skin that is deficient in L3PSP expression and measure the effect on epidermal proliferation, apoptosis and hair follicle morphogenesis. Lay summary: Overall we plan to ascertain whether a protein normally thought to function in basic cellular amino acid metabolism may also regulate the growth and maintenance of hair follicles by stimulating programmed cell death pathways in skin cells. In doing so, the studies outlined in this proposal will have important implications for hair follicle biology and epithelial cell survival in general. [unreadable] [unreadable] [unreadable]